CN101987843A - Method for synthesizing halofuginone hydrobromide and analogues thereof - Google Patents
Method for synthesizing halofuginone hydrobromide and analogues thereof Download PDFInfo
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- CN101987843A CN101987843A CN2010102577231A CN201010257723A CN101987843A CN 101987843 A CN101987843 A CN 101987843A CN 2010102577231 A CN2010102577231 A CN 2010102577231A CN 201010257723 A CN201010257723 A CN 201010257723A CN 101987843 A CN101987843 A CN 101987843A
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- 0 CCOC(*(CCC1)C=C1*1CCCC1)O Chemical compound CCOC(*(CCC1)C=C1*1CCCC1)O 0.000 description 3
- ROPVALDOHOXSQQ-DIFFPNOSSA-N CCCC[C@@H]([C@H](C)CC(CN(C=Nc(cc1Br)c2cc1Cl)C2=O)=O)O Chemical compound CCCC[C@@H]([C@H](C)CC(CN(C=Nc(cc1Br)c2cc1Cl)C2=O)=O)O ROPVALDOHOXSQQ-DIFFPNOSSA-N 0.000 description 1
- VWQXCLBFGRMQJC-UHFFFAOYSA-N CCOC(N(CCC1)CC1=O)=O Chemical compound CCOC(N(CCC1)CC1=O)=O VWQXCLBFGRMQJC-UHFFFAOYSA-N 0.000 description 1
- BBQQULRBTOMLTC-UHFFFAOYSA-N O=C1CN(Cc2ccccc2)CCC1 Chemical compound O=C1CN(Cc2ccccc2)CCC1 BBQQULRBTOMLTC-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a method for synthesizing halofuginone hydrobromide and analogues thereof. The halofuginone hydrobromide is shown in the following formula, wherein, R1 refers to trichloroethyl, 2,2-trichloroethyl dimethyl, ethyl, benzyl, tertiary butyl, C1-C6 alkyls, monosubstituted or polysubstituted phenyl, and monosubstituted or polysubstituted benzyl; and R2, R3 and R4 respectively refer to hydrogen, chlorine, bromine, iodine, methoxyl, C1-C4 alkyls, C1-C6 alkenyls, and C1-C6 alkynyls, and R2 and R3, or R3 and R4, or R4 and R5 are -OCH2O-. In the invention, cheap and easily-obtained N-alkyl-substituted-piperidone hydrochlorides are used as raw materials to establish an efficient and concise universal method for synthesizing halofuginone hydrobromide. The method of the invention has the advantages of short route, high efficiency, mild reaction condition, high yield and good product purity, is convenient to operate and avoids the application of metal reagents; therefore, the method is applicable to industrialization.
Description
Technical field
The present invention relates to the synthetic method of a kind of halofuginone hydrobromide hydrobromate and analogue thereof.
Background technology
Halofuginone hydrobromide (Halofuginone, WR237645) 7-bromo-6-chloro-3-[(3-hydroxy-2-piperidinyl)-2-oxopropyl]-4 (3H)-quinazolinone}, have another name called bromine chlorine halofuginone hydrobromide, halogen quinoline ketone, halofuginone.Be a kind of quinazoline ketones alkaloid---halo derivatives of from plant Changshan (Dichroa febrifuga, in China), separating of febrifugin(e) (Febrifugine):
Its hydrobromate (Halofuginone hydrobromide, " speed is red ", Stenorol
) or lactic acid salt (Halofuginone lactate, Halocur
) (Bioorganic ﹠amp; Medicinal Chemistry Letters, 2007,7 (15), 4140-4143) extensively sell as commodity.It is added in the feed of livestock, be respectively applied for prevention and treatment coccidiosis of chicken (Coccidiosis in Chicken) [2] and the dysentery (Diarrhea) of the calf that causes by Cryptosporidium (Cryptosporidium) (US.Pat.No.4340596).1967, reported first such as Kantor were mixed in feed with the concentration of 3ppm speed is red, 5 kinds of Amy otology (Eimeriidae) Eimerias (Eimeria) coccidia of killing chicken have efficiently (Adv.Pharmacol.Chemother, 1973,10,221-293).1974, isolating worm strain test newly such as Foure, Bennejean and Yvore from the field, prove that this medicine all has efficiently (Recueil de Medecine Veterinaire to multiple coccidia, 1974,150 (6), 495-503). at present, the chemism of halofuginone hydrobromide treatment is not clear, mainly is that the sporozoite (Sporozoite) that produces in first and second generation schizont (Merozoite) of coccidia and the egg capsule is had tangible inhibitory or killing effect.
Two chiral centres are arranged on the piperidine ring of halofuginone hydrobromide, have a pair of diastereomer---trans halofuginone hydrobromide (trans-Halofuginone, i.e. halofuginone hydrobromide, Halofuginone) and the cis halofuginone hydrobromide (cis-Halofuginone, Isohalofuingone).The biological activity of trans halofuginone hydrobromide is far above cis halofuginone hydrobromide (Chem.Pharm.Bull.1998,46 (1), 1-5; J.Org.Chem., 1973,38,1937-1940), in organic solvent, the process of experience Michael-Retro Michael Addition reaches isomerization equilibrium (J.Am.Chem.Soc., 1949,71,1048-1054; J.Org.Chem., 1973,38,1933-1936; Chem.Pharm.Bull.1998,46 (1), 1-5).
For the stability that improves halofuginone hydrobromide and prevent isomerization, people make hydrobromate or lactic acid salt as commerce product (WO 03/070153) with halofuginone hydrobromide.
Only there is a route to realize suitability for industrialized production about the synthetic of halofuginone hydrobromide hydrobromate at present.That is:
Summary of the invention:
Purpose of the present invention aims to provide a kind of synthetic method of new halofuginone hydrobromide hydrobromate (Halofuginone hydrobromide), overcomes the defective of prior art.With N-alkyl replacement-3-piperidone hydrochloride cheap and easy to get is raw material, sets up the method for efficient, succinct synthetic halofuginone hydrobromide hydrobromate (Halofuginone hydrobromide).This synthetic method route is brief, efficient, and easy to operate, mild condition has been avoided the use of metal reagent, the overall yield height, and good product purity is applicable to industrialization.
The reactions steps that the synthetic method of halofuginone hydrobromide hydrobromate provided by the invention (Halofuginone hydrobromide) comprises (in the statement hereinafter, specific synthetic product is according to the numbering in the structural formula, represents with Arabic numerals):
R
1Be three chloroethyls, 2, the alkyl of 2-dimethyl three chloroethyls, ethyl, benzyl, the tertiary butyl, C1-C6, the single replacement or (substituting group are: the alkynyl of the alkyl of C1-C4, the thiazolinyl of C1-C6, C1-C6, the alkoxyl group of C1-C4, nitro, halogen etc.) such as polysubstituted phenyl, single replacement or polysubstituted benzyls; Compound 11 is 5,6,7, and the 8-position is quinazolone that replace or non-replacement, R
2, R
3, R
4And R
5Be respectively the alkyl of hydrogen, chlorine, bromine, iodine, methoxyl group, C1-C4, the thiazolinyl of C1-C6, the alkynyl of C1-C6, R
2And R
3, or R
3And R
4, or R
4And R
5For-OCH
2O-etc.; R
6And R
7Be respectively the alkyl of C1-C4, perhaps R
6And R
7For-(CH
2)
3-,-(CH
2)
4-etc.; R
8Replacement or unsubstituted alpha-halogen alkene for C1-C6.
Concrete steps are:
Step 1: compound 2 reacts in alkaline solution, the inert organic solvents extraction, and the saturated common salt water washing, drying leaves standstill.Be spin-dried for solvent and obtain red thick liquid, 61pa is collected in underpressure distillation, and 95 ℃ of cuts obtain the white solid of compound 3.Said inert organic solvents is preferably ethyl acetate, ether, methylene dichloride etc.Said alkali can be inorganic or organic alkali, is preferably sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, triethylamine etc.
Step 2: compound 3, organic or mineral alkali, in inert organic solvents, under-20 ℃ of-50 ℃ of conditions, react, add acyl chlorides or acid anhydrides then.Reaction adds saturated Na after finishing
2CO
3Solution stirs.Ethyl acetate extraction, the saturated common salt water washing, drying leaves standstill.Be spin-dried for solvent and obtain light yellow viscous liquid, underpressure distillation promptly obtains the white solid of compound 4.Said inert organic solvents is acetonitrile, tetrahydrofuran (THF), ethyl acetate etc.; Said alkali is salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, triethylamine, pyridine etc.Said acyl chlorides or acid anhydrides are trichloroethyl chloroformate, Acetyl Chloride 98Min., chloroformic acid benzyl ester, tert-Butyl dicarbonate, acrylate chloride, chloroformic acid-2,2-dimethyl trichloro ethyl ester etc.
Step 3: compound 4 and organic bases in inert organic solvents, reflux 5-12 hour, be cooled to room temperature, be spin-dried for, drain solvent, obtain the scarlet viscous fluid, promptly compound 5.With compound 5 in inert organic solvents with the alpha-halogen olefine reaction, add saturated Na
2CO
3Solution revolves except that behind most of solvent, ethyl acetate extraction, and the saturated common salt water washing, drying leaves standstill.Be spin-dried for the red-brown thick liquid of solvent, obtain compound 6.Said inert organic solvents is a benzene,toluene,xylene etc., and said alkali is tetramethyleneimine, piperidines, diethylamine etc.Said alpha-halogen alkene is allyl bromide 98, chlorallylene, 2-chloro-3-bromopropylene, 1-bromo-2-butylene, 3-chloro-2-methoxyl group propylene etc.
Step 4: compound 6 in inert organic solvents with reductive agent-20 ℃ of-50 ℃ of reactions, the shrend reaction of going out, ethyl acetate extraction, be spin-dried for colourless liquid, promptly compound 7.Said inert organic solvents is methyl alcohol, ethanol etc.; Said reductive agent is sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride and trifluoroacetyl oxygen base sodium borohydride, lithium borohydride etc.
Step 5: compound 7 and NBS in the mixed solvent of water and inert organic solvents ,-20 ℃ of-50 ℃ of reactions, add saturated Na
2S
2O
3, stir, add saturated Na
2CO
3Solution, organic phase is got in the inert organic solvents extraction, uses saturated Na again
2CO
3Solution washing, the saturated common salt water washing, drying leaves standstill.Be spin-dried for solvent, obtain weak yellow liquid, promptly compound 8.Inert organic solvents is preferably ethyl acetate.
Step 6: compound 8 is dissolved among the DMF with alkali, adds compound 11 at-20 ℃ of-50 ℃ of stirring reactions, adds distilled water, ethyl acetate extraction, saturated common salt water washing, standing and drying.Be spin-dried for ethyl acetate, underpressure distillation eliminates DMF, obtains white solid, and promptly compound 9.Said alkali can be preferably Anhydrous potassium carbonate, anhydrous sodium carbonate etc. for inorganic or organic alkali.
Step 7: compound 9 is dissolved in inert solvent and the distilled water mixed solvent, adds Glacial acetic acid and zinc powder, the stirring at room reaction, with reaction soln with distilled water diluting after, add anhydrous K
2CO
3, ethyl acetate extraction.Merge organic phase, with the washing of 2mol/L hydrochloric acid soln.Merge water, add anhydrous K
2CO
3, ethyl acetate extraction, the saturated common salt water washing, drying leaves standstill.Be spin-dried for solvent and get white solid, promptly compound 10.Said inert solvent is tetrahydrofuran (THF), methyl alcohol, ethanol, acetic acid etc.
Step 8: compound 10 is dissolved in the ethanol, and heating for dissolving is cooled to room temperature, leaves standstill, and crystallization gets white crystalline powder, and promptly compound 12.
Step 9: compound 12 is dissolved in HBr (40% aqueous solution) and H
2In the mixed solution of O, the solid dissolving is left standstill, ageing, and suction filtration, obtaining white solid is compound 13.HBr (40% aqueous solution) and H
2The volume ratio of O is 1: 10-50.
The present invention is a raw material with N-alkyl replacement-3-piperidone hydrochloride cheap and easy to get, sets up the method for efficient, succinct synthetic halofuginone hydrobromide hydrobromate (Halofuginone hydrobromide).This synthetic method route is brief, efficient, and easy to operate, mild condition has been avoided the use of metal reagent, the overall yield height, and good product purity is applicable to industrialization.
Embodiment
Below the invention will be further described in conjunction with the embodiments again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.Among the following embodiment, fusing point is not calibrated, and yield is without optimization.
The preparation of embodiment 1 compound 3
Take by weighing 200g compound 2, be dissolved in the 500mL distilled water, take by weighing 40g NaOH and be dissolved in the 100mL distilled water, pour in the solution of compound 2.Stir, ethyl acetate extraction 3 times, the saturated common salt water washing once, drying leaves standstill.Be spin-dried for solvent and obtain red thick liquid, 61pa is collected in underpressure distillation, and 95 ℃ of cuts get colourless liquid, and argon shield places the refrigerator after fixing, obtains the 160g white solid, and promptly compound 3, productive rate 95.4%.
1H NMR (400MHz, CDCl
3) δ 7.26 (m, 5H), 3.59 (s, 2H), 3.01 (s, 2H), 2.69-2.61 (m, 2H), 2.37 (t, J=6.9Hz, 2H), 1.96 (d, J=6.2Hz, 2H).
The preparation of embodiment 2 compounds 14
Take by weighing 52g compound 3, the 40g anhydrous K
2CO
3, place the 1L two-mouth bottle, add the 300mL acetonitrile, add 116g (about 78mL) trichloroethyl chloroformate.After reaction finishes, add the saturated Na of 50mL
2CO
3Solution.Revolve and remove most of CH
3Behind the CN, ethyl acetate extraction 5 times, the saturated common salt water washing once, drying leaves standstill.Be spin-dried for solvent and obtain light yellow viscous liquid, 21pa is collected in underpressure distillation, and 135 ℃ of cuts obtain the 64g white solid, and promptly compound 14, productive rate 84.8%, 58 ℃ of fusing points.
1H NMR (400MHz, CDCl
3) δ 4.77 (s, 2H), 4.14 (d, J=15.1Hz, 2H), 3.74 (dd, J=10.2,5.7Hz, 2H), 2.53 (t, J=6.7Hz, 2H), 2.06 (dt, J=12.8,6.6Hz, 2H).
The preparation of embodiment 3 compounds 15
Operation is with embodiment 2, and difference is compound 3 and excess acetyl chloride, generates compound 15.
1HNMR(400MHz，CDCl
3)δ4.16(d，J＝7.0Hz，2H)，4.06(s，2H)，3.65(t，J＝5.3Hz，2H)，2.49(t，J＝6.7Hz，2H)，2.06-1.95(m，2H)，1.27(t，J＝7.0Hz，3H).
The preparation of embodiment 4 compounds 15
Compound 3 (60mmol, 11.4g) with tert-Butyl dicarbonate (13.7g, 63mmol), 10%Pd/C 2g feeds hydrogen reaction in the 360mL ethyl acetate, filters palladium carbon, adds shrend and goes out, dry organic phase is spin-dried for solvent, underpressure distillation generates compound 16.
1H?NMR(400MHz，CDCl
3)δ3.97(s，2H)，3.55(s，2H)，2.43(t，J＝6.5Hz，2H)，2.35-1.91(m，2H)，1.43(s，9H).
The preparation of embodiment 5 compounds 18
Take by weighing 12.9g compound 14, place the 500mL two-mouth bottle, add 270mL benzene and 8mL tetramethyleneimine, reflux after having reacted, is cooled to room temperature, is spin-dried for, and drains solvent, obtains the scarlet viscous fluid, and promptly compound 5.Compound 5 is transferred in the 500mL two-mouth bottle, adds the 300mL acetonitrile, and 9.4g (about 6.3mL) 2-chloro-3-bromopropylene (compound 19), reflux 3h adds the saturated Na of 20mL
2CO
3Solution revolves except that behind most of solvent, ethyl acetate extraction 5 times, and saturated common salt water washing 1 time, drying leaves standstill.Be spin-dried for the red-brown thick liquid of solvent, post separates, and obtains 18, two step of 10.3g compound overall yield 62.8%.
1H NMR (400MHz, CDCl
3) δ 5.27 (s, 2H), 5.22 (s, 1H), 4.79 (s, 2H), 4.21 (s, 1H), 3.31 (m, 1H), 2.84 (d, J=6.3Hz, 2H), 2.55 (dd, J=13.3,6.5Hz, 2H), 2.05 (dd, J=11.7,4.8Hz, 2H).
The preparation of embodiment 6 compounds 20
Operation is with embodiment 3, and difference is compound 14 and tetramethyleneimine reaction, and then with allyl bromide 98 reacting generating compound 20.Productive rate 63.5%,
1H NMR (400MHz, CDCl
3) 5.11 (d, J=16.0Hz, 2H), 4.78 (s, 2H), 4.66 (s, 1H), 4.18 (s, 1H), 3.26 (s, 1H), 2.85 (d, J=4.8Hz), 2.52 (d, J=4.8Hz, 2H), 2.04 (s, 2H).
The preparation of embodiment 7 compounds 22
Operation is with embodiment 3, and difference is compound 15 and tetramethyleneimine reaction, and then with 2-chloro-3-bromopropylene reacting generating compound 22.Productive rate 78%,
1H NMR (400MHz, CDCl
3) 5.35-5.28 (m, 2H), 4.85 (s, 1H), 4.14 (s, 3H), 2.94 (m, 1H), 2.69-2.60 (m, 2H), 2.55-2.30 (m, 2H), 1.98 (s, 2H), 1.26 (t, J=7.0Hz, 3H).
The preparation of embodiment 8 compounds 24
Operation is with embodiment 3, and difference is compound 15 and tetramethyleneimine reaction, and then with allyl bromide 98 reacting generating compound 24.Productive rate 64%,
1H NMR (400MHz, CDCl
3) 5.73 (s, 1H), 5.06 (s, 2H), 4.62-4.60 (m, 1H), 4.36 (m, 3H), 3.19 (s, 1H), 2.22 (m, 4H), 1.95-1.90 (m, 2H), 1.26 (s, 3H).
The preparation of embodiment 9 compounds 25
Take by weighing 7g compound 18, place the 250mL round-bottomed bottle, add 100mL methyl alcohol, add 1.37g NaBH
4, after having reacted, add 10mL distilled water, revolve and remove most of methyl alcohol, ethyl acetate extraction, be spin-dried for colourless liquid 7g, productive rate 99%.
1H NMR (300MHz, CDCl
3) δ 5.20 (s, 2H), 5.12-3.92 (m, 3H), 3.92-3.57 (m, 1H), 3.45 (s, 1H), 2.86 (s, 1H), 2.77 (m, 2H), 1.87 (s, 1H), 1.74 (s, 1H), 1.55 (s, 2H).
The preparation of embodiment 10 compounds 26
Take by weighing 2.62g compound 25 and be dissolved in 100mL CH
3In CN and the 50mL distilled water, add 1.45g NBS (bromo-succinimide), add saturated Na
2S
2O
3Saturated Na is used in the cancellation reaction
2CO
3Wash 3 times, saturated common salt water washing 1 time, drying leaves standstill.Be spin-dried for solvent, obtain weak yellow liquid 3.02g, promptly compound 26, productive rate 99%.
1H NMR (400MHz, CDCl
3) δ 5.07-4.58 (m, 4H), 4.46 (d, J=4.6Hz, 1H), 4.02 (ddd, J=47.3,26.8,8.6Hz, 2H), 3.66-3.49 (m, 2H), 3.25-2.80 (m, 2H), 2.60-2.42 (m, 1H), 2.17-1.68 (m, 4H).
The preparation of embodiment 11 compounds 27
Take by weighing 3.558g compound 26 and 1.583g Anhydrous potassium carbonate and be dissolved among the 30mL DMF, add compound 29 (chlorine bromine quinazolone) and stir, after react, adding 10mL distilled water, ethyl acetate is diluted, extract 3 times, the saturated common salt water washing once, standing and drying.Be spin-dried for ethyl acetate, underpressure distillation eliminates DMF, obtains the 5.1g white solid, i.e. compound 27 productive rates 99%.
1H NMR (400MHz, DMSO) δ 8.28 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 6.40 (s, 1H), 4.83 (s, 1H), 4.74 (s, 2H), 4.27 (d, J=13.8Hz, 2H), 4.14 (d, J=13.9Hz, 1H), 3.64-3.54 (m, 2H), 2.01 (d, J=8.1Hz, 2H), 1.68 (s, 1H), 1.48 (s, 1H), 1.35 (s, 2H).
The preparation of embodiment 12 compounds 28
Take by weighing 2.668g compound 27 and be dissolved in tetrahydrofuran (THF) and the distilled water mixed solvent, inject the 25mL Glacial acetic acid, add the 4.4g zinc powder, stir 2.5h. with reaction soln with distilled water diluting after, add anhydrous K
2CO
3, ethyl acetate extraction.Merge organic phase, with 2mol/L hydrochloric acid soln washing 2 times.Merge water, add anhydrous K
2CO
3, ethyl acetate extraction 3 times, saturated common salt water washing 1 time, drying leaves standstill.Be spin-dried for solvent and get white solid 1.61g, promptly compound 28, productive rate 86%.
1H NMR (400MHz, CDCl
3) δ 8.27 (s, 1H), 8.23 (s, 1H), 7.94 (s, 1H), 4.31 (d, J=13.9Hz, 1H), 4.13 (d, J=13.9Hz, 1H), 3.85 (d, J=2.0Hz, 1H), 3.27 (s, 1H), 2.94 (d, J=11.0Hz, 1H), 2.49 (t, J=11.3Hz, 1H), 2.11-1.97 (m, 2H), 1.84-1.69 (m, 2H), 1.50 (dd, J=18.6,9.5Hz, 2H).
The preparation of embodiment 13 compounds 1
Take by weighing 1.49g compound 28 and be dissolved in the ethanol, back flow reaction stops heating and is cooled to room temperature, suction filtration, and washing with alcohol gets white crystalline powder, i.e. compound 1 (rac-Halofuginone).
1H?NMR(400MHz，d
6-DMSO)δ8.24(s，1H)，8.23(s，1H)，8.16(s，1H)，5.00(d，J＝2.0Hz，2H)，4.76(d，J＝5.8Hz，1H)，3.01-2.94(m，2H)，2.79(d，J＝11.9Hz，1H)，2.64(td，J＝8.8，3.6Hz，1H)，2.49-2.29(m，2H)，1.90(dd，J＝8.1，3.8Hz，1H)，1.57(d，J＝12.6Hz，1H)，1.41-1.29(m，1H)，1.21(ddd，J＝15.9，13.1，3.4Hz，1H).
The preparation of embodiment 14 halofuginone hydrobromide hydrobromates
Get 0.483g compound 1 and be dissolved in 2mL HBr/H
2O (40%) and 50mL H
2In the mixed solution of O, solid dissolves gradually, separates out precipitation then, ageing, and suction filtration obtains white solid 0.528g, i.e. the halofuginone hydrobromide hydrobromate.243 ℃ of productive rate 80%. fusing points.
1H NMR (300MHz, D
2O) δ 8.06 (s, 1H), 8.02 (s, 1H), 7.78 (s, 1H), 4.97 (d, J=7.4Hz, 3H), 3.60 (s, 1H), 3.37 (d, J=7.5Hz, 1H), 3.20 (s, 1H), 2.92 (d, J=13.3Hz, 1H), 1.98 (s, 1H), 1.86 (s, 2H).
Claims (9)
1. the synthetic method of halofuginone hydrobromide hydrobromate and analogue thereof is characterized in that the step that it comprises:
R
1Be three chloroethyls, 2, the alkyl of 2-dimethyl three chloroethyls, ethyl, benzyl, the tertiary butyl, C1-C6, the single replacement or polysubstituted phenyl, single replacement or polysubstituted benzyl,, substituting group is: the alkynyl of the alkyl of C1-C4, the thiazolinyl of C1-C6, C1-C6, alkoxyl group, nitro or the halogen of C1-C4; R
2, R
3, R
4And R
5Be respectively the alkyl of hydrogen, chlorine, bromine, iodine, methoxyl group, C1-C4, the thiazolinyl of C1-C6, the alkynyl of C1-C6, R
2And R
3, or R
3And R
4, or R
4And R
5For-OCH
2O-; R
6And R
7Be respectively the alkyl of C1-C4, perhaps R
6And R
7For-(CH
2)
4-,-(CH
2)
4-; R
8Replacement or unsubstituted alpha-halogen alkene for C1-C6;
Concrete steps are:
Step 1: compound 2 reacts in alkaline solution, the inert organic solvents extraction, and the saturated common salt water washing, drying leaves standstill; Be spin-dried for solvent and obtain red thick liquid, 61Pa is collected in underpressure distillation, and 95 ℃ of cuts obtain the white solid of compound 3;
Step 2: compound 3, organic or mineral alkali, in inert organic solvents, under-20 ℃ of-50 ℃ of conditions, react, add acyl chlorides or acid anhydrides then; Reaction adds saturated Na after finishing
2CO
3Solution stirs; Ethyl acetate extraction, the saturated common salt water washing, drying leaves standstill.Be spin-dried for solvent and obtain light yellow viscous liquid, underpressure distillation promptly obtains the white solid of compound 4;
Step 3: compound 4 and organic bases are in inert organic solvents, and reflux after having reacted, is cooled to room temperature, is spin-dried for, and drains solvent, obtains the scarlet viscous fluid, and promptly compound 5; With compound 5 in inert organic solvents with the alpha-halogen olefine reaction, add saturated Na
2CO
3Solution revolves except that behind most of solvent, ethyl acetate extraction, and the saturated common salt water washing, drying leaves standstill; Be spin-dried for the red-brown thick liquid of solvent, obtain compound 6;
Step 4: compound 6 in inert organic solvents with reductive agent-20 ℃ of-50 ℃ of reactions, the shrend reaction of going out, ethyl acetate extraction, be spin-dried for colourless liquid, promptly compound 7;
Step 5: compound 7 and bromo-succinimide (NBS), in the mixed solvent of water and inert organic solvents, at-20 ℃ of-50 ℃ of reactions, saturated Na
2S
2O
3Saturated Na is used in the cancellation reaction
2CO
3Washing, the saturated common salt water washing, drying leaves standstill; Be spin-dried for solvent, obtain weak yellow liquid, promptly compound 8; Said organic solvent is preferably acetonitrile, and inert organic solvents is an ethyl acetate;
Step 6: take by weighing compound 8 and be dissolved in the dimethyl formamide (DMF), add compound 11 ,-20 ℃ of-50 ℃ of stirrings, after having reacted, add distilled water, ethyl acetate dilution, extraction, saturated common salt water washing, standing and drying with alkali; Be spin-dried for ethyl acetate, underpressure distillation eliminates DMF, obtains white solid, and promptly compound 9; Said alkali is Anhydrous potassium carbonate, anhydrous sodium carbonate;
Step 7: compound 9 is dissolved in inert solvent and the distilled water mixed solvent, adds Glacial acetic acid and zinc powder, the stirring at room reaction; With reaction soln with distilled water diluting after, add anhydrous K
2CO
3, ethyl acetate extraction merges organic phase, with the washing of 2mol/L hydrochloric acid soln, merges water, adds anhydrous K
2CO
3, ethyl acetate extraction, the saturated common salt water washing, drying leaves standstill, and is spin-dried for solvent and gets white solid, and promptly compound 10;
Step 8: compound 10 is dissolved in the ethanol, and heating for dissolving is cooled to room temperature, leaves standstill, and crystallization gets white crystalline powder art, and promptly compound 12;
Step 9: compound 12 is dissolved in the 40%HBr aqueous solution and H
2In the O mixed solution, the solid dissolving, ageing, suction filtration, drying, obtaining white solid is compound 13; HBr (40% aqueous solution) and H
2The volume ratio of O is 1: 10-50.
2. synthetic method according to claim 1 is characterized in that the said inert organic solvents of step 1) is ethyl acetate, ether, methylene dichloride; Said alkali is sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, triethylamine.
3. synthetic method according to claim 1 is characterized in that step 2) said inert organic solvents is acetonitrile, tetrahydrofuran (THF), ethyl acetate; Said alkali is salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, triethylamine, pyridine; Said acyl chlorides or acid anhydrides are trichloroethyl chloroformate, Acetyl Chloride 98Min., chloroformic acid benzyl ester, tert-Butyl dicarbonate, acrylate chloride, chloroformic acid-2,2-dimethyl trichloro ethyl ester; Said inert organic solvents is acetonitrile, tetrahydrofuran (THF), ethyl acetate; Said alkali is salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, triethylamine, pyridine.
4. synthetic method according to claim 1 is characterized in that the said inert organic solvents of step 3) is a benzene,toluene,xylene, and said alkali is tetramethyleneimine, piperidines, diethylamine; Said alpha-halogen alkene is allyl bromide 98, chlorallylene, 2-chloro-3-bromopropylene, 2-bromo-2-butylene, 3-chloro-2-methoxyl group propylene.
5. synthetic method according to claim 1 is characterized in that the said inert organic solvents of step 4) is methyl alcohol, ethanol etc.; Said reductive agent is sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, trifluoroacetyl oxygen base sodium borohydride, lithium borohydride.
6. synthetic method according to claim 1 is characterized in that the said inert organic solvents of step 5) is an ethyl acetate.
7. synthetic method according to claim 1 is characterized in that the structure of compound 4 is:
8. synthetic method according to claim 1 is characterized in that the structure of described compound 6 is:
9. synthetic method according to claim 1 is characterized in that the structure of described compound 7,8,9 is respectively:
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| CN103204799A (en) * | 2013-05-06 | 2013-07-17 | 青岛农业大学 | (2S,3R)-1-substituted benzyl-2-allyl-3-hydroxypiperidine and preparation method thereof |
| CN103275063A (en) * | 2013-06-19 | 2013-09-04 | 重庆威鹏药业有限公司 | Method for preparing halofuginone hydrobromide |
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